Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery

Background: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). Methods: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. Results: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). Conclusions: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission

The impact of metabolic endotoxaemia on the browning process in human adipocytes

Background: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Methods: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre-and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Results: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). Conclusions: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

Relationships of dietary patterns with body composition in older adults differ by gender and PPAR-γ Pro12Ala genotype

Dietary patterns may better capture the multifaceted effects of diet on body composition than individual nutrients or foods. The objective of this study was to investigate the dietary patterns of a cohort of older adults, and examine relationships of dietary patterns with body composition. The influence of a polymorphism in the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene was considered. The Health, Aging and Body Composition (Health ABC) Study is a prospective cohort study of 3,075 older adults. Participants’ body composition and genetic variation were measured in detail. Food intake was assessed with a semi-quantitative food frequency questionnaire (Block Dietary Data Systems, Berkeley, CA), and dietary patterns of 1,809 participants with complete data were derived by cluster analysis. Six clusters were identified, including a ‘Healthy foods’ cluster characterized by higher intake of low-fat dairy products, fruit, whole grains, poultry, fish and vegetables. An interaction was found between dietary patterns and PPAR-γ Pro12Ala genotype in relation to body composition. While Pro/Pro homozygous men and women in the ‘Healthy foods’ cluster did not differ significantly in body composition from those in other clusters, men with the Ala allele in the ‘Healthy foods’ cluster had significantly lower levels of adiposity than those in other clusters. Women with the Ala allele in the ‘Healthy foods’ cluster differed only in right thigh intermuscular fat from those in other clusters. Relationships between diet and body composition in older adults may differ by gender and by genetic factors such as PPAR-γ Pro12Ala genotype

Influência do resfriamento dinâmico na medição da tensão limite de escoamento

Non-Newtonian fluids may present several complex characteristics, such as viscoelasticity, plasticity and thixotropy. Understanding the behaviour of these materials is essential to facilitate its applicability, since many of them are present in daily life, such as gels, chocolate, and mayonnaise. The material studied on the present work was an waxy crude oil. The oil, present in reservoirs located in deep water, when subjected to low temperatures during production shutdowns, precipitates its paraffin, creating a structure which may be very resistant to flow. Thus, the formed material may represent a great difficulty to production restart. The design of pumps and compressors used in these systems depend on a rheological property called yield stress and therefore, it is essential to obtain reliable values of this rheological parameter. However, the complex behaviour, and the dependence of the crude oil characteristics on the shearing and temperature history make this a challenging task. Besides these, other factors may influence the measurement of yield stress, as the effect of wall slip and if the cooling is static or dynamic. This work shows the variation of yield stress for tests with dynamic cooling. The imposition of a stress during cooling caused the reduction in yield stress 0. Increasing the imposed stress, 0 decreased until it reached a minimum. Next, it was noticed an increase in yield stress with increasing imposed stress. The experiments carried out in this work were made in a commercial stress control rheometer. The effect of wall slip was tested by comparing smooth and rough geometries and it was verified signs of its presence, with the reduction of yield stress for smooth geometries. The equation of Weissenberg-Rabinowitsch, used for correction of the inhomogeneity of the shear stress along the radius geometry, seemed to be not necessary for the demonstrated results.Fluidos não newtonianos podem apresentar diversas características complexas, como a viscoelasticidade, plasticidade e tixotropia. Entender o comportamento de materiais tão complexos é fundamental para facilitar sua aplicabilidade, já que muitos estão presentes no cotidiano das pessoas, como géis, chocolate e maionese. O material estudado no presente trabalho foi um petróleo parafínico. O petróleo, presente em bacias localizadas em águas profundas, quando submetido a baixas temperaturas durante paradas de produção, precipita suas parafinas dando origem a uma estrutura que pode ser muito resistente ao escoamento. Dessa forma, o material formado pode representar uma grande dificuldade para o reinício da produção. O dimensionamento das bombas e compressores utilizados para retomada da produção depende de uma propriedade reológica denominada tensão limite de escoamento e, por isso, é fundamental obter valores confiáveis desse parâmetro reológico. No entanto, o comportamento complexo, e a dependência das características do petróleo com o histórico de cisalhamento e temperatura tornam a tarefa desafiadora. Outros fatores podem influenciar na medição da tensão limite de escoamento, como o efeito do escorregamento na parede do sensor da geometria e se o resfriamento é estático ou dinâmico. Este trabalho mostra a variação da tensão limite de escoamento para ensaios com resfriamento dinâmico. A imposição de tensão durante o resfriamento causou a redução da tensão limite de escoamento 0. Elevando-se a tensão imposta, 0 reduziu até atingir um valor mínimo. Em seguida, percebeu-se um aumento da tensão limite de escoamento com o aumento da tensão imposta. Os experimentos realizados neste trabalho foram feitos em um reômetro comercial do tipo tensão controlada (“stress controlled”). O efeito de escorregamento da amostra foi testado comparando geometrias com superfícies lisas e ranhuradas e foi possível verificar sinais de sua presença, com a redução da tensão limite de escoamento para geometrias lisas. A equação de Weissenberg-Rabinowitsch, utilizada para correção da não homogeneidade da tensão de cisalhamento ao longo do raio da geometria, mostrou-se não necessária para os resultados demonstrados

Systemic triglycerides as a key determinant of TLR regulated inflammatory risk in human adipose tissue post bariatric surgical intervention and weight loss

Bariatric surgery can lead to a quick reversal in type 2 diabetes mellitus (T2DM) status. However, despite this reversal inflammatory responses may still persist via activation of Toll-like receptors (TLR) within adipose tissue (AT); with triglycerides (TGs) noted as a potential mediator of such inflammation. Therefore the aims of these studies were to understand the impact of TG changes, pre- and post-bariatric surgery, on TLR expression in ex vivo AT and the in vitro effects of triglyceride rich lipoprotein (VLDL), on TLR expression in isolated human differentiated pre-adipocytes. Obese, T2DM, female subjects (age: 54.6±6.6 years, BMI pre (41.2±5.5 kg/m2) and 6 months post-surgery (36.05±5.16 kg/m2; n=30) underwent bariatric surgery (banding (n=8); plication (n=14); and biliopancreatic diversion (n=8)). Biochemical data and abdominal subcutaneous AT (AbdSc AT) samples were taken during surgery and 6 months post-surgery. Real-time PCR assessed TLR expression. Human differentiated pre-adipocyte Chub S7 cells were used to examine transcriptional effects of VLDL on TLR expression. Following surgical intervention, BMI (P<0.001), blood glucose (P<0.001), insulin (P<0.001), HOMA-IR (P<0.001), TG (P<0.05), cholesterol (P<0.001), and LDL-cholesterol (P<0.05) were significantly improved. There was a significant reduction in TLR4 mRNA post-surgery (P<0.01) irrespective of surgery type. It was also noted that subjects with the greatest drop (55.5% reduction) in TGs post-surgery (P<0.001) showed a significant correlated reduction in TLR4 mRNA expression (P<0.001). In vitro treatment of differentiated Chub S7 cells highlighted VLDL induced TLR4 mRNA expression (P<0.05).There is a reduction in AT inflammation as denoted by TLR expression. The reduction in AT inflammation appears dependent on how successfully subjects reduce their serum triglyceride, which is supported by in vitro studies. These studies suggest that bariatric surgery lead to metabolic improvement with weight loss, whilst dietary intervention is still required to ensure TGs reduce to reduce inflammation.N/

Unfolded protein response in adipose tissue of obese diabetic women significantly improved 6 months post bariatric surgery, irrespective of malabsorptive or bypass operation type and correlates with plasma glucose concentration

In obesity, excess nutrients and an increased demand for protein synthesis contribute to unfolded proteins accumulating within the endoplasmic reticulum and consequent activation of unfolded protein response (UPR). UPR in adipose tissue (AT) is critical to the initiation and integration of inflammation and insulin signalling pathways in obese and type 2 diabetes mellitus (T2DM) patients. The aim of this study was to examine whether novel malabsorptive or bypass bariatric surgery in obese women with T2DM leads to reduction in UPR. Abdominal subcutaneous (AbSc) AT was isolated from 30 Caucasian obese T2DM women aged 54.1±1.3 (mean±S.E.M.) years, BMI 41.21±1.0 kg/m2, that had undergone bariatric surgery of malabsorptive; gastric band (n=9) or novel gastric plication (n=13), or bypass; biliopancreatic diversion (n=8) type. Biopsies and anthropometric data were collected at the time of surgery and 6 months post-surgery. UPR markers were measured by qRT-PCR and western blotting and correlation analysis was performed. Six months post-operation all subjects significantly reduced body weight (P<0.001) with mean excess BMI lost 33.4±2.4%. Anthropometric measurements were significantly improved; fat mass, HbA1c, glucose, insulin, HOMA-IR, and total cholesterol (all P<0.001). ATF6, IRE1α, XBP1s, ATF4, and CHOP10 mRNAs and ATF6, pIRE1α, XBP1s, Calnexin and Bip proteins were all significantly (P<0.05) reduced post-surgery irrespective of operation type. Correlations between UPR mRNAs were strengthened post-surgery for ATF4 and CHOP10 (P=0.041–P<0.001) and IRE1α and ATF6 (P=0.853–P<0.001). Post-surgery plasma glucose correlated significantly (P=0.034) with XBP1s mRNA. This study highlights that bariatric surgery induced weight loss is coupled with improved glucose homeostasis and reduced UPR expression in AT. Furthermore post weight loss there are enhanced associations identified between UPR and XBP1 in AT and plasma glucose which may arise due to improved glucose homeostasis. This suggests UPR regulation in AT is linked to plasma glucose levels which aligns to metabolic health.N/